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Antagonistic variant virus prevents wild-type virus-induced lethal immunopathology.

Hunziker L, Recher M, Ciurea A, Martinic MM, Odermatt B, Hengartner H, Zinkernagel RM - J. Exp. Med. (2002)

Bottom Line: However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus-host relationships via inhibiting T cell-mediated immunopathology is unclear.Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus.This may play a role in poorly cytopathic long-lasting virus carrier states in humans.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. hunziker@pathol.unizh.ch

ABSTRACT
Altered peptide ligands (APLs) and their antagonistic or partial agonistic character-influencing T cell activation have mainly been studied in vitro Some studies have shown APLs as a viral escape mechanism from cytotoxic CD8(+) T cell responses in vivo. However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus-host relationships via inhibiting T cell-mediated immunopathology is unclear. Here, we evaluated a recently described CD4(+) T cell escape lymphocytic choriomeningitis virus (LCMV) variant that in vitro displayed antagonistic characteristics for the major histocompatibility complex class II-restricted mutated epitope. Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus. The results illustrate that a coinfecting APL-expressing virus can shift an immunopathological virus-host relationships in favor of host survival. This may play a role in poorly cytopathic long-lasting virus carrier states in humans.

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LCMV-APL prevents lethal immunopathology of LCMV-WEWT and LCMV-Docile. (c) Smarta1 mice were infected with 200 pfu LCMV-WEWT (▾), LCMV-Docile (▪), LCMV-Docile plus 200 pfu LCMV-WEAPL (○), LCMV-WEWT plus 200 pfu LCMV-WEAPL (▿), LCMV-WEWT plus 2 × 104 pfu LCMV-WEAPL (□), or LCMV-Docile plus 2 × 104 LCMV-WEAPL. (a) Survival rate (n = 4 per group) and (b) bodyweight reduction are shown. (c) The activation of blood CD4+ T cells was measured by CD69 up-regulation and (d) CD62L down-regulation. (e) Virus titers were measured in blood. (b–e) 200 pfu LCMV-Docile (n = 3), LCMV-WEWT (n = 3). Coinfection of groups is n = 4 per group. Statistically significant difference between the following groups (P < 0.05): (c) ▪ versus □ at days 4 and (c and d) 7 and (d) ▪ versus ○ at day 7; (c) ▴ versus ▾ at days 4, (d) 7, and (c) 12 and ▴ versus ▿ at (c) days 4, (d) 7, and (c) 12.
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fig3: LCMV-APL prevents lethal immunopathology of LCMV-WEWT and LCMV-Docile. (c) Smarta1 mice were infected with 200 pfu LCMV-WEWT (▾), LCMV-Docile (▪), LCMV-Docile plus 200 pfu LCMV-WEAPL (○), LCMV-WEWT plus 200 pfu LCMV-WEAPL (▿), LCMV-WEWT plus 2 × 104 pfu LCMV-WEAPL (□), or LCMV-Docile plus 2 × 104 LCMV-WEAPL. (a) Survival rate (n = 4 per group) and (b) bodyweight reduction are shown. (c) The activation of blood CD4+ T cells was measured by CD69 up-regulation and (d) CD62L down-regulation. (e) Virus titers were measured in blood. (b–e) 200 pfu LCMV-Docile (n = 3), LCMV-WEWT (n = 3). Coinfection of groups is n = 4 per group. Statistically significant difference between the following groups (P < 0.05): (c) ▪ versus □ at days 4 and (c and d) 7 and (d) ▪ versus ○ at day 7; (c) ▴ versus ▾ at days 4, (d) 7, and (c) 12 and ▴ versus ▿ at (c) days 4, (d) 7, and (c) 12.

Mentions: In vitro, APL effects are usually observed with specific CD4+ T cells at 10–100-fold excess of the APL peptide against a submaximal WT peptide concentration. To examine APL effects in vivo during an infection we used the gp61-75R peptide that displayed the antagonistic activity in vitro at a 100-fold excess against the WT gp61 peptide (19). The dose of WT peptide cannot be determined during a virus infection, but it is probably high. With the LCMV-WEAPL we could now test the effects of APL not only with peptide treatment but also by using the APL virus. The effects of LCMV-WEAPL were assessed in vivo by coinfecting Smarta1 mice with different doses of LCMV-WEAPL and LCMV WT strains LCMV-WEWT or LCMV-Docile at a ratio of 1:1 to 1:100, respectively. The infection of Smarta1 mice with 200 pfu LCMV-Docile and 200 pfu LCMV-WEAPL could not prevent lethal immunopathology (Fig. 3 a). The body weight reduction was comparable (Fig. 3 b), whereas CD4+ T cell activation was significantly reduced 7 d after infection in regard to CD62L down-regulation, but no statistical difference in CD69 up-regulation could be observed (Fig. 3, c and d). Mice exhibited signs of systemic disease upon infection with 200 pfu LCMV-WEWT plus 200 pfu LCMV-WEAPL, but the mortality rate was reduced to 20% (Fig. 3, a–d). The infection of mice with 200 pfu LCMV-Docile plus 2 × 104 pfu LCMV-WEAPL resulted in a wasting disease but the mice recovered after 30 d (Fig. 3, a and b). Compared to infection with LCMV-Docile alone, the coinfection resulted in a statistically significant delay of the tg CD4+ T cell activation with regard to CD69 up-regulation and CD62L down-regulation (Fig. 3, c and d). After infection with 200 pfu LCMV-WEWT plus a 100-fold excess of LCMV-WEAPL (2 × 104 pfu), the bodyweight loss was considerably less severe and mice were clinically in much better condition (Fig. 3, a and b). In addition, the tg CD4+ T cells were statistically significantly less activated with regard to CD69 up-regulation at days 4 and 12 (Fig. 3, c and d). All mice became chronic LCMV carriers, although the initial virus load in the blood at 4 d after infection was reduced in LCMV-WEAPL–infected mice coinfected with LCMV-Docile compared to mice infected with LCMV-Docile alone, although not statistically significant (Fig. 3 e).


Antagonistic variant virus prevents wild-type virus-induced lethal immunopathology.

Hunziker L, Recher M, Ciurea A, Martinic MM, Odermatt B, Hengartner H, Zinkernagel RM - J. Exp. Med. (2002)

LCMV-APL prevents lethal immunopathology of LCMV-WEWT and LCMV-Docile. (c) Smarta1 mice were infected with 200 pfu LCMV-WEWT (▾), LCMV-Docile (▪), LCMV-Docile plus 200 pfu LCMV-WEAPL (○), LCMV-WEWT plus 200 pfu LCMV-WEAPL (▿), LCMV-WEWT plus 2 × 104 pfu LCMV-WEAPL (□), or LCMV-Docile plus 2 × 104 LCMV-WEAPL. (a) Survival rate (n = 4 per group) and (b) bodyweight reduction are shown. (c) The activation of blood CD4+ T cells was measured by CD69 up-regulation and (d) CD62L down-regulation. (e) Virus titers were measured in blood. (b–e) 200 pfu LCMV-Docile (n = 3), LCMV-WEWT (n = 3). Coinfection of groups is n = 4 per group. Statistically significant difference between the following groups (P < 0.05): (c) ▪ versus □ at days 4 and (c and d) 7 and (d) ▪ versus ○ at day 7; (c) ▴ versus ▾ at days 4, (d) 7, and (c) 12 and ▴ versus ▿ at (c) days 4, (d) 7, and (c) 12.
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fig3: LCMV-APL prevents lethal immunopathology of LCMV-WEWT and LCMV-Docile. (c) Smarta1 mice were infected with 200 pfu LCMV-WEWT (▾), LCMV-Docile (▪), LCMV-Docile plus 200 pfu LCMV-WEAPL (○), LCMV-WEWT plus 200 pfu LCMV-WEAPL (▿), LCMV-WEWT plus 2 × 104 pfu LCMV-WEAPL (□), or LCMV-Docile plus 2 × 104 LCMV-WEAPL. (a) Survival rate (n = 4 per group) and (b) bodyweight reduction are shown. (c) The activation of blood CD4+ T cells was measured by CD69 up-regulation and (d) CD62L down-regulation. (e) Virus titers were measured in blood. (b–e) 200 pfu LCMV-Docile (n = 3), LCMV-WEWT (n = 3). Coinfection of groups is n = 4 per group. Statistically significant difference between the following groups (P < 0.05): (c) ▪ versus □ at days 4 and (c and d) 7 and (d) ▪ versus ○ at day 7; (c) ▴ versus ▾ at days 4, (d) 7, and (c) 12 and ▴ versus ▿ at (c) days 4, (d) 7, and (c) 12.
Mentions: In vitro, APL effects are usually observed with specific CD4+ T cells at 10–100-fold excess of the APL peptide against a submaximal WT peptide concentration. To examine APL effects in vivo during an infection we used the gp61-75R peptide that displayed the antagonistic activity in vitro at a 100-fold excess against the WT gp61 peptide (19). The dose of WT peptide cannot be determined during a virus infection, but it is probably high. With the LCMV-WEAPL we could now test the effects of APL not only with peptide treatment but also by using the APL virus. The effects of LCMV-WEAPL were assessed in vivo by coinfecting Smarta1 mice with different doses of LCMV-WEAPL and LCMV WT strains LCMV-WEWT or LCMV-Docile at a ratio of 1:1 to 1:100, respectively. The infection of Smarta1 mice with 200 pfu LCMV-Docile and 200 pfu LCMV-WEAPL could not prevent lethal immunopathology (Fig. 3 a). The body weight reduction was comparable (Fig. 3 b), whereas CD4+ T cell activation was significantly reduced 7 d after infection in regard to CD62L down-regulation, but no statistical difference in CD69 up-regulation could be observed (Fig. 3, c and d). Mice exhibited signs of systemic disease upon infection with 200 pfu LCMV-WEWT plus 200 pfu LCMV-WEAPL, but the mortality rate was reduced to 20% (Fig. 3, a–d). The infection of mice with 200 pfu LCMV-Docile plus 2 × 104 pfu LCMV-WEAPL resulted in a wasting disease but the mice recovered after 30 d (Fig. 3, a and b). Compared to infection with LCMV-Docile alone, the coinfection resulted in a statistically significant delay of the tg CD4+ T cell activation with regard to CD69 up-regulation and CD62L down-regulation (Fig. 3, c and d). After infection with 200 pfu LCMV-WEWT plus a 100-fold excess of LCMV-WEAPL (2 × 104 pfu), the bodyweight loss was considerably less severe and mice were clinically in much better condition (Fig. 3, a and b). In addition, the tg CD4+ T cells were statistically significantly less activated with regard to CD69 up-regulation at days 4 and 12 (Fig. 3, c and d). All mice became chronic LCMV carriers, although the initial virus load in the blood at 4 d after infection was reduced in LCMV-WEAPL–infected mice coinfected with LCMV-Docile compared to mice infected with LCMV-Docile alone, although not statistically significant (Fig. 3 e).

Bottom Line: However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus-host relationships via inhibiting T cell-mediated immunopathology is unclear.Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus.This may play a role in poorly cytopathic long-lasting virus carrier states in humans.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zurich, Switzerland. hunziker@pathol.unizh.ch

ABSTRACT
Altered peptide ligands (APLs) and their antagonistic or partial agonistic character-influencing T cell activation have mainly been studied in vitro Some studies have shown APLs as a viral escape mechanism from cytotoxic CD8(+) T cell responses in vivo. However, whether infection or superinfection with a virus displaying an antagonistic T cell epitope can alter virus-host relationships via inhibiting T cell-mediated immunopathology is unclear. Here, we evaluated a recently described CD4(+) T cell escape lymphocytic choriomeningitis virus (LCMV) variant that in vitro displayed antagonistic characteristics for the major histocompatibility complex class II-restricted mutated epitope. Mice transgenic for the immunodominant LCMV-specific T helper epitope that usually succumb to wild-type LCMV-induced immunopathology, survived if they were simultaneously coinfected with antagonistic variant but not with control virus. The results illustrate that a coinfecting APL-expressing virus can shift an immunopathological virus-host relationships in favor of host survival. This may play a role in poorly cytopathic long-lasting virus carrier states in humans.

Show MeSH
Related in: MedlinePlus